This proposed research is intended to provide information that will help clarify the interactions between transmitter systems associated with the basal ganglia, the site for control of mental states and locomotion. The studies described herein are designed to elucidate the significance of the changes in substance P (SP) concentration within the substantia nigra which occur following the enhancement or blockade of dopaminergic systems. I have previously reported that decreases in the activity of the nigral-striatal dopamine (DA) pathway with chronic haloperidol treatment or 6-hydroxydopamine lesions results in significant reductions in nigral SP levels, while increased DA activity associated with subacute amphetamine or acute L-DOPA treatments results in elevated concentrations of nigral SP. These SP changes in the substantia nigra likely reflect dopaminergic influence on the striatal-nigral SP neurons which are thought to have an excitatory feedback function on nigral-striatal DA projections. I propose that the drug-induced decreases and increases of nigral SP concentrations reflect, respectively, increases and decreases in the activity of the striatal-nigral SP pathway. However, this interpretation requires confirmation with another technique which can more directly measure activity changes in the SP transmitter system. Thus, I will conduct a set of studies employing tissue slices to measure in vitro release of SP from substantia nigras exposed in vivo and in vitro to the dopaminergic drugs mentioned above. The results of these studies will be correlated with the in vivo drug-induced changes which occur in nigral SP concentrations and will help clarify the interactions between DA and SP systems associated with the basal ganglia.